Abstract: Anti-apoptotic Bcl-2 and Bcl-xL proteins are key regulators of apoptosis and attractive new targets for cancer chemotherapy. The design and development of highly potent and specific small-molecule inhibitors of these proteins is a very challenging task in medicinal chemistry since it is involved in targeting protein-protein interaction. Employing a structure-based scaffold design strategy, we have designed a new class of potent, specific small-molecule inhibitors of Bcl-2/Bcl-xL that can bind with subnanomolar Ki values and function as potent antagonists of Bcl-2/Bcl-xL in functional assays. A 1.4 ? resolution crystal structure of a lead compound complexed with Bcl-xL has provided a basis for further optimization. Our most effective inhibitors induce robust apoptosis in cancer cells lines that depend upon Bcl-2/Bcl-xL for survival and achievecomplete tumor regression in the H146xenograft model. The design, synthesis and evaluation for this new class of compounds will be described.

Structure-based design of a new class of potent Bcl-2/Bcl-xL inhibitors

243rd National Meeting (2012)

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